Research described in application will take advantage of recent conceptual developments in the mechanism(s) of cellular immune recognition to devise novel modalities of immunotherapy for immunoglobulin (Ig)-expressing B cell malignancies. B cell malignancies express tissue-specific differentiation antigens that, as is the case for Ig, may have B cell- subset-specific or tumor cell-specific antigenic determinants that are clonally distributed. Development of strategies that either enhance cellular immune recognition of tumor-specific Ig and/or break self- tolerance to B cell-subset-specific Ig antigenic determinants may have immunotherapeutic applications that transcend those applicable only for B cell tumors. To this end, we will: 1) examine the immunotherapeutic utility of in vivo transient transfection of somatic cells using DNA vaccines encoding Ig V genes or Ig V gene fragments with or without appended signal sequences of genes encoding accessory cytokines, such as IL-2 or IL-4; 2) evaluate human lymphoblastoid cell lines transfected with such Ig-encoding DNA vaccines for their capacity to stimulate syngeneic Ig V gene-directed cytolytic T cells lines (CTL) in vitro; 3) investigate modalities of active immunotherapy for a transplantable murine B cell hybridoma expressing rheumatoid factor (RF) encoded by murine Ig variable region genes (V genes) that have not diversified substantially from the germline DNA; 4) evaluate the short and long-term effects on transgene expression of active Ig-directed immunotherapy in mice transgenic for human IgM RFs; and 5) clinically investigate the in vivo immunogenicity of transfectoma-derived IgM for B cell leukemia populations expressing Ig with shared cross reactive idiotypic determinants. Through these studies we may develop novel and clinically effective active immunotherapeutic regimens for human neoplasia.